title: Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning.
abstract: BACKGROUND
  Caveolae, lipid-rich microdomains of the sarcolemma, localize and enrich cardiac-protective signaling molecules. Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of caveolar formation. We hypothesized that cardiac myocyte-specific overexpression of Cav-3 would enhance the formation of caveolae and augment cardiac protection in vivo.
  
  
  RESULTS
  Ischemic preconditioning in vivo increased the formation of caveolae. Adenovirus for Cav-3 increased caveolar formation and phosphorylation of survival kinases in cardiac myocytes. A transgenic mouse with cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) showed enhanced formation of caveolae on the sarcolemma. Cav-3 OE mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to transgene-negative mice. Endogenous cardiac protection in Cav-3 OE mice was similar to wild-type mice undergoing ischemic preconditioning; no increased protection was observed in preconditioned Cav-3 OE mice. Cav-3 knockout mice did not show endogenous protection and showed no protection in response to ischemic preconditioning. Cav-3 OE mouse hearts had increased basal Akt and glycogen synthase kinase-3beta phosphorylation comparable to wild-type mice exposed to ischemic preconditioning. Wortmannin, a phosphoinositide 3-kinase inhibitor, attenuated basal phosphorylation of Akt and glycogen synthase kinase-3beta and blocked cardiac protection in Cav-3 OE mice. Cav-3 OE mice had improved functional recovery and reduced apoptosis at 24 hours of reperfusion.
  
  
  CONCLUSIONS
  Expression of caveolin-3 is both necessary and sufficient for cardiac protection, a conclusion that unites long-standing ultrastructural and molecular observations in the ischemic heart. The present results indicate that increased expression of caveolins, apparently via actions that depend on phosphoinositide 3-kinase, has the potential to protect hearts exposed to ischemia/reperfusion injury.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, USA.
authors.forename: Yasuo M
authors.initials: YM
authors.lastname: Tsutsumi
authors.forename: Yousuke T
authors.initials: YT
authors.lastname: Horikawa
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Jennings
authors.forename: Michael W
authors.initials: MW
authors.lastname: Kidd
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.forename: Paul A
authors.initials: PA
authors.lastname: Insel
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D021941:Caveolae / Q000502:physiology / Q000648:ultrastructure; D051244:Caveolin 3 / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012508:Sarcolemma / Q000502:physiology / Q000648:ultrastructure
chemical_list: C495548:Cav3 protein, mouse; D051244:Caveolin 3; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3